Diamine compounds



United States Patent Ofihoe This invention relates to diamine compounds. More particularly, the invention relates to diamine compounds which are represented by the following structural formula CH: lower alkyl lower alkyl mates!) Fatented Nov. 13, 1962 incorporating them in conventional ointments and lotions for topical application.

The following examples are illustrative of the invention. All temperatures are in degrees centigrade.

5 Example I 5 tsps. of Raney nickel catalyst were added to a solution of 250 g. (1.3 mols) of fl-ionone and 200 g. (5.3 mols) of anhydrous methylamine in 400 ml. of ethanol. The mixture was hydrogenated at 150 and 1500 p.s.i. The catalyst was filtered olf, the excess methylamine and methanol were distilled OE and the residual oil was fracwherein m is 0 or 1.

The lower alkyl groups in the above formula include straight chain and branch chain groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl and heptyl. The alkylene groups include straight chain and branched chain divalent saturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms in the chain. The products may contain varying amounts of water of hydration. The anions are negative ions from organic or inorganic acids such as the hydrohalic or other mineral acids, arylsulfonic acids, etc., preferably bromide, chloride, iodide or p-toluene-sulfonate.

A preferred group of compounds within the above class may be represented by the following structural formula CH3 CH3 tionated in vacuo to obtain [1-methyl-3-(2,6,6-trimethy1- l-cyclohexen-l-yl) propyl]methylamine, B.P. 117-1 19 To 62 g. (0.3 mol) of [l-methyl-3-(2,6,6-trimethyl-1- cyclohexen-l-yl)propyl]methylamine, dissolved in 38 ml. (0.75 mol) of 90% formic acid, was added 28.5 ml. (0.35 mol) of 35% formaldehyde. The solution was stirred on a steam bath for 3 hours and the excess formaldehyde and formic acid were then distilled off. The residual oil was made strongly alkaline with 50% potassium hydroxide and extracted with ether. The ether extract was washed with water, dried with potassium carbonate and the ether was then distilled off. The residual oil was fractionated in vacuo to obtain [1-methyl-3-(2,6,6-trimethyl-l-cyclohexen-l yl(propyl]- dimethylamine, B.P. 97-99".

wherein n is an integer from 2 to l0, inclus ive.

The novel compounds of this invention are prepared by reacting two molecular proportions of a [1-methyl-3- (2,6,6 trimethyl-l-cyclohexen-1-yl)butyl]dilower alkylamine or a [2-methyl-4-(2,6,6-trimethyl-l-cyclohexen-1- yl)butyl] dilower alkylamine with one molecular proportion of an a,w-dihaloalkane, preferably in a solvent such as ethanol or acetonritrile, While heating, say at reflux temperature. The [1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)propyl]dilower alkylamine and [2-methyl-4- 2,6,6-trimethyl-l-cyclohexenl-yl) butyl] dilower alkylmine starting materials can be prepared by first reductively condensing fi-ionone or 4-(2,6,6-trimethyl-1-cyclohexen-l-yl)-2-methyl-2-buten-l-al with a lower alkylamine and then alkylating the products thus obtained, forexample, with formic acid and formalydeyde. Certain intermediates are novel and are also within the scope of this invention.

The compounds of this invention are useful as antimicrobial agents. They are active against bacteria and fungi, such as Trichophyton mentagrophytes and Micro sporon lanosum, and are also active against Trichomonas vaginalis. They are particularly useful as local antiseptics and'may be applied topically, for example by An aliquot of the above free base when neutralized with oxalic acid dissolved in ethanol gave the crystalline [1 methyl 3 (2,6,6-trimethyl-l-cyclohexen-l-yl)- propyl]dimethylamine monooxalate, M.P. 189190. An aliquot of the above free base when neutralized with alcoholic hydrogen chloride gave the crystalline [1- methyl 3 (2,6,6-trimethyl-l-cyclohexen-l-yl)propyl]dimethyl-amine hydrochloride, M.P. 69-71 (crystallized from acetonitrile-ether).

13.4 g. (0.06 mol) of [l-methyl-3-(2,6,6-trimethyl-1- cyclohexen-l-yl)]dimethylamine and 6.1 g. (0.03 mol) of 1,3-dibromo-propane were dissolved in 150 ml. abso lute ethanol and refluxed for 72 hours. The colorless solution was concentrated to a syrup at steam temperature and under water vacuum. The syrup was triturated with ether and crystallized from acetone-ether to obtain N,N'-bis-[1-methyl-3-(2,6,6-trimethyl-l-cyclohexen-l-yD-propyl] N,N-dimethyl- 1,3-propanediamine bis(metho'bromide) dihydrate, M.P. 195196.

Example 2 aoeeos s 3 41' the procedure described in Example 1 and the product 3 hours and the excess formaldehyde and formic acid crystallized from acetonit'rile-acetone. The N,N-biswere then distilled off. The residual oil was made strong- {l-methyl-3-(2,6,6-trimethyl 1 cyclohexen-l-yDpropyH- 1y alkaline with 50% potassium hydroxide and extracted N,N-dimethyl 1,4 butanediamine bis(methobromide) with ether. The ether extract was washed with water, hemihydrate thus obtained melted at" 231-233 with dec. 5 dried with potassium carbonate and the ether distilled off.

The residual oil was fractionated in vacuo to obtain N-[2- rnethyl-4-(2,6,6 trimethyl 1 cylohexen 1 yl)butyl]- 13.4 g. (0.06 mol) of ll-methyl-S-(2,6,6-trimethyl-ldj thyl ine, B P

Example 3 y -ybp py l y and g- 23.7 g. (0.1 mol) of N-[2-methyl-4-(2,6,6-trimethyl-1- 11101) of Lidibfomopemane Were l'eacwd according to 10 cyclohexen-=1-yl)butyl]dimethylarnine and 12.2 g. (0.05 the pllocedllle described in Example 11 The Crude P mol} of 1,6-dibromohexane were dissolved in 200 ml. of was crystallized fl'Qm acemflitfilfi-ethel' t0 Obtain aoetonitrile and treated according to the procedure de- Y trimethyl 1 cyclcheXen-lscribed in Example 4. The N,N'-bis-[2-methyl-4-(2,6,6 v )-p 9py 1- y -p b s(methtrimethyl 1 cyclohexen ,1 yl)butyl]-N,N'-dimethyl- Obfomlde) sesqulhydfate, melted at 'd l5 1,6 heXanediamine bis(met-hobromide) dihydrate obtained Example 4 by this procedure was recrystallized from isopropanol,

M.P. 225-226", with dec. 13.4 g. (0.06 mol) of [l-methyl-3-(2,6,6-trimethyl-1- cyclohexen-l-yDpropyl]dimethylarnine and 7.3 g. (0.03 Example 7 mol) of 1,6-dibromohexane were dissolved in 60 ml. of 23] g (0.71 mol) f 1 1 3- 2 i h 1.1 warm acetonitrile and refiuxed. After 15 minutes crystals i 1 udi h l i 9.4 g. (0.05 formed The mlxture Was f l E refluxed far 18 mol) of 1,2-dibromoethane were dissolved in 200 ml. of Q and Cooled- The ?3 acetonitrile and treated according to the procedure detnmethyl l -Y )P 1 1- dunethylscribed in Example 4. The N,N'-bis-{l-methyl-3'-(2,6,6- L-hexanediarmne bis (methobromide) monohydrate crys- 25 trimethyl 1 cyclohexen 1 1 1 i 1 tals th s o'btam we e filtered o washed Wlth a f 1,2-ethylenediamine bis(methobrornide)rnonohydrate obmum of cold acetonitrile and dried, MP. 245-246 with mined by this procedure was crystallized from acetoneether, M.P. 157-158", with dec.

Example 5 p Example. 8. 13.4 g. (0.06 mol) of [l methyl-3-(2,6,6-trrmethyl-1- cyclohexen l-yhpropyl]dimethylamine and7.0 g. (0.03 H101) 0f y y mol) of 1,7-dibromoheptane were reacted according to y l h ynp pyn hyl mi e and gthe procedure described in Example 1, Th N N' bi mol) of l,10-dibromodecane were reacted according to El--methyl-3-(2,6,6-trimethyl 1 cyclohexen 1 yDprothe procedure described in Example 4. The N,-N-bispyl] -N,N'-dimethyl 1,7 heptanediamine bis (methobro- Y y 1 cyclohexen 1 Y )P mide)dihydrate thus obtained Was recrystallized from PY y -decaflediflmifle bisfinethflbroethanol-petroleum ether, M.P. 218-219. rnide) sesquihydrate obtained by this procedure was crystallized from ethanol-acetone-ether, M.P. 190-192. Example 6 We claim: 3 tsps. of Raney nickel catalyst were'added to a solu- 40 1. A compound represented by the formula 0% /CH3 lower alkyl lower alkyl CH: CH!

/C\ lower alkyl\ /lower alkyl /O.\ H2? (fl3-CH OH;([1H(CHz)m1TT-(OHg)nlTI(CH2)mfi3HGHgCH2- one H3O 0-011, CH3 x X CH: HeC-O on,

o o H H,

tion of 200 g. (1 mol) of 4-(2,6,6-trimethyl-l-cyclohexen- 5 wherein m represents an integer from 0 to 1, n represents 1-yl)-2-methyl-2-buten-1-al and g. of anhydrous an integer from 2 to 10, and X is an anion selected from methylamine in 300 ml. of methanol. The mixture was the group consisting of anions of mineral acids and hydrogenated at and 1500 p.s.i. The catalyst was arylsulfonic acids. filtered off, and the excess methylarnine and methanol 2. A compound selected by the formula CH\a '/CH: Cg, /CHa /G\ (CH3): (CH3): /C\ H1O CCH2CHzCH-N'(CH:1)n-N CH-GHa-CHg-Q OH: H2O c-om one halogen halogen one ens-o on, c c H7 H3 distilled off. To the residual oil, dissolved in 114 1121. wherein it is an integer from 2v to 10, inclusive, and haloof 90% formic acid, were added 855 ml. of 35% forrngen represents a member of the group consisting of chloaldehyde, The solution was stirred on a steam bath for rine, bromine and iodine.

3. A compound represented by the formula wherein n isv an integer from 2 to 10, inclusive.

4. N,N'-bis-[1 methyl-3-(2,6,G-trimethyl-l-cyclohexen- 1-yl)propyl] N,N dimethyl 1,6 hexanediamine-bis- (lower alkyl halide), said halide being selected from the group consisting of chloride, bromide and iodide.

5. N,N'-bis-[1 methyl-3-(2,6,6-trimethyl-I-cyclohexen- 1-yl)pr0pyl] -N,N'-dimethyl-1,6-hexanediamine bis (methobromide).

6. N,N'-his-[1 methyl-3- (2,6,G-trimethyl-l-cyclohexen- 1-y1)propy1] -N,N'-dimethy1-1,5-pentanediamine his (lower alkyl halide), said halide being selected from the group consisting of chloride, bromide and iodide.

7. N,N'-bis-[1 methyl-3-(2,6,6-trimethyl-l-cyclohexenl-yl) propyl]-N,N-dimethyl-1,5-pentanediamine bis (methobromide).

8. A compound selected from the group consisting of a base represented by the formula wherein m represents an integer from 0 to 1 and mineral acid, oxalic acid, and arylsulfonic acid addition salts thereof.

9. [1-methy1-3-(2,6,6-trimethyl 1 cyclohexen-l-yD- propyl] -dimethylamine.

10. [1-methyl-3-(2,6,6-trimethyl 1 cyclohexen-l-yD- propyl] -dimethylamine oxalate.

11. [2-methyl-4-(2,6,6-trimethyl 1 cyclohexen-l-yD- butyl] -dimethylamine.

References Cited in the file of this patent UNITED STATES PATENTS 2,736,746 Goldberg et al Feb. 28, 1956 2,736,747 Goldberg et a1 Feb. 28, 1956 2,767,168 Cheney Oct. 16, 1956 2,933,530 Kralt et a1 Apr. 19, 1960 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Nou 3 O64 O39 November 13, 1962 Moses Wolf Goldberg et a1,

It is hereby certified that err or appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l line 52,, for "butyl" read propyl line 6% for "formalydeyde" read formaldehyde column 2 l ne 29 for (035 mol) read (033 mol) column 4 line 54,, for "selected" read represented Signed and sealed this 8th day of October 1963.,

(SEAL) Attest:

EDWIN L, REYNOLDS ERNEST W. SWIDER Attesting Officer AC t i ng Commissioner of Patents 

1. A COMPOUND REPRESENTED BY THE FORMULA
 8. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A BASE REPRESENTED BY THE FORMULA 